B1 antagonists

Target and Target Class: Bradykinin receptor 1 (B1); GPCR

Indication: Inflammatory and neuropathic pain

Rationale

Kinins are pro-inflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes, namely B1 and B2, have been identified and characterized. Both receptors belong to the family of G-protein-coupled receptors (GPCR).

Whereas B2 receptors are constitutively present in normal tissues, B1 receptors are normally expressed at a very low level under physiological conditions. However, B1 receptors are considerably up-regulated by several pro-inflammatory mediators such as cytokines and following tissue injury. Therefore, B1 receptors appear to be important mediators of painful stimuli during chronic inflammation.

Two G-protein-coupled receptors, the B1 and the B2 receptors, are part of the system. Other enzymes such as ACE (also known as kininase II), neutral endopeptidase and aminopeptidase-P, cleave kinins at different sites, which results in their complete pharmacological inactivation. ACE, angiotensin-converting enzyme; AM, aminopeptidase M; CP, carboxypeptidases N and M (= kininase I); HK, high-molecular-mass kininogen; LK, low-molecular-mass kininogen; PK, plasma kallikrein; TK, tissue kallikrein. (Schematic reproduced with permission from François Marceau et al. (2004) Nature Reviews Drug Discovery 3, 845 - 852)

The therapeutic interest in B1 receptors as a potential target for the treatment of inflammatory pain is supported by several studies using B1 receptor antagonists which have been shown to be active in a number of disease-relevant models. In addition, in light of the discrete up-regulation of the B1 receptor in both the spinal cord and brain under certain conditions, B1 antagonists also hold the potential for the treatment of neurogenic inflammatory states and neuropathic pain. Support for the role of B1 receptors in inflammation and pain also comes from studies in B1 receptor knock-out models where a decreased response to nociceptive and pro-inflammatory stimuli is observed.

While this body of evidence makes the B1 receptor an attractive target in the treatment and management of pain, recent findings indicate that B1 antagonists may also be of therapeutic interest in other indications.

Status

Evotec has identified active B1 antagonists from a combination of high throughput screening and pharmacophore studies. The most advanced series of compounds is progressing through lead optimization and shows good progress towards clinical development.